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This impressive study from Cornelius Gross’ group again highlights the importance of appropriate immune surveillance during brain development. They show that an insufficient number of microglia in the developing CNS results in synaptic pruning deficits and leads to decreased functional connectivity that persists until adulthood; this in turn causes behavioral changes in mice.

It is tempting to speculate that, conversely, an overactive immune response could lead to the removal of too many synapses and thereby cause functional deficits. This may be what happens during brain inflammation, and we have previously shown that microglia activated with low concentrations of Aβ (nanomolar) will phagocytose and thereby destroy neurons and their synapses in vitro. Importantly, this loss of synapses and death of neurons could be blocked by inhibiting phagocytosis, indicating that during inflammation phagocytosis can execute neuronal death and synaptic loss (Neher et al., 2011; Neniskyte et al., 2011). We could also show that after focal brain ischemia (which also has relevance for vascular dementia), microglia kill stressed but viable neurons by eating them, and that mice deficient in phagocytosis had reduced functional deficits (Neher et al., 2013).

However, whether excessive phagocytosis of synapses and/or neurons is relevant for AD remains to be established, particularly because microglia in AD models may have reduced phagocytic capacity (Krabbe et al., 2013). However, the study by Krabbe et al. used relatively large particles and looked at their uptake by plaque-associated microglia. It would be interesting to know if this also applies to small structures such as synapses and to microglia that are not directly engaged in phagocytosing plaques. To examine these differential effects will be tricky, as any manipulation of phagocytosis will likely affect both amyloid deposition and uptake of neuronal structures unless specific pathways for one or the other can be identified.